HER2 is a member of the epidermal growth factor receptor family and is amplified/over-expressed in approximately 15-20% of breast cancers. HER-2 is a non-ligand member of the ERbB family and becomes activated mainly by overexpression which leads to spontaneous homo-dimerization, phosphorylation of the c-terminal part of Her2 and activation of downstream signaling events in a ligand-independent manner. In addition, Her2 also undergoes proteolytic cleavage which results in the release of the extracellular domain and the production of a truncated membrane fragment, p95, which is constitutively active. It has been hypothesized that the phosphorylated form of HER2 (pHER2) more accurately reflects the signaling and functional activity of the HER2 protein and recent evidence has demonstrated an association between pHER2 and HER2 gene copy number as assessed by fluorescent in situ hybridization (FISH).
The over-expression of HER2 is an independent adverse prognostic factor and currently the best predictive factor for the activity of trastuzumab, an anti-HER2 monoclonal antibody therapy. Currently, HER2 status is most frequently determined by immunohistochemical detection of HER2 protein expression on the cell membrane surface or by FISH of the HER2 gene copy number in fixed tissue using locus-specific probes for the HER2 gene and chromosome 17. These methods continue to be problematic due to issues with intra and inter laboratory reproducibility and pre-analytic variable such as fixation time. FISH is considered to be the reference standard and more accurately predicts response to therapy, but is technically demanding, expensive, and requires specialized equipment.
Trastuzumab used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in metastatic patients, as well as halving the recurrence rate and improving survival in early breast cancer. Although over-expression is a useful predictor for response, only about one-third of patients, however, initially respond to trastuzumab monotherapy and the majority of initial responders demonstrate disease progression within 1 year of treatment initiation. Saez et al., 2006 and others have proposed that a terminally truncated form of the receptor, p95HER2, which remains membrane bound and tyrosine-phosphorylated, provides a mechanism for resistance to the monoclonal antibody trastuzumab.
Recently, Frogne et al., 2009 demonstrated that in a multivariate setting, levels of the phosphorylated form of Her2 (pHer2) in hormone receptor positive, primary tumors was an independent predictor for poor disease-free and overall survival when tested against tumor size, grade, nodal status and Her2. The results suggest that in trastuzumab-resistant disease, new strategies and compounds, including alternative therapeutic options should be considered such as small molecule dual kinase inhibitors (e.g., lapatinib), and selective targets within the angiogenic pathway (e.g., bevacizumab).
Prior studies demonstrated that the expression of truncated p95HER2 protein correlated with extent of lymph node involvement and metastatic disease, suggesting it represents a marker for more aggressive disease. Since trastuzumab blocks HER2 activity by binding to a part of the receptor that is located on the outside of the cell; the hypothesis is that the truncated p95HER2 (and/or the pHer2 full length receptor) remains active and may respond to inhibitors of tyrosine kinase activity, such as lapatinib. Scaltriti et al. 2007 showed that treatment of p95HER2 expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream pAKT and inhibited cell growth.